The mechanisms by which inflammation of the bladder could lead to chronic pain remain a mystery. Interstitial Cystitis (IC) is an enigmatic disorder associated with chronic inflammation whose primary manifestations are bladder pain and irritative voiding. IC affects up to 90,000 individuals in the United States, yet therapy for the disease is inadequate, due in part to this lack of understanding of the underlying pathophysiological causes and consequences associated with the disorder. This proposal will test three hypotheses concerning the pathophysiological consequences of bladder inflammation on visceral afferents. The hypotheses to be tested are: 1) Infectious, mechanical and chemical irritation of the bladder alter baseline activity and/or the response characteristics of sensory nerve firing to distension. 2) Inflammation alters the structure and connectivity of bladder afferents, helping to explain the alteration in firing and/or threshold. 3) The mechanisms linking structural and functional changes in the nociceptive pathways from the bladder reflect an alteration in the ongoing, trophic determination of neural function by target-derived trophic factors including nerve growth factor (NGF). These hypotheses will be tested by a multidisciplinary approach in that rat involving bladder irritation, electrophysiological recording of peripheral nerve activity, quantitative morphometry of retrogradely labeled neurons, two-site ELISA assay of NGF levels in bladder tissues, bioassay of other neurotrophins produced by inflamed bladder and determination of the regulation of NGF synthesis by cultured bladder smooth muscle and urothelial cells. The results of these studies promise to reveal novel mechanisms behind the cellular and molecular basis for bladder inflammation and sequelae. The results have the potential to suggest novel areas for improved intervention or treatment in painful disorders of the lower urinary tract including IC.